Modern medicine has relied heavily on synthetically or chemically produced drugs to treat or prevent diseases and conditions in patients. However, in recent times there has been more emphasis on the use of protein-based drugs (also known as “biologics” or biopharmaceuticals”), to prevent and treat diseases and conditions, or to restore or maintain normal body functions of patients. Protein-based drugs are pharmaceuticals based on proteins or portions of proteins such as peptides. Protein-based drugs have become increasingly important in recent years with the advent of high throughput screening and proteomics.
Protein-based drugs do present a difficult challenge for pharmaceutical scientists in that these molecules tend to be large and bulky, making it difficult for them to gain access to target sites of the human body. Protein-based drugs may also be very sensitive to the acid and digestive enzymes of the gut, which makes them unsuitable for oral administration. Accordingly, protein-based drugs, such as insulin, have to be administered parenterally by injection to be efficacious. Patients may need to self-administer several injections each day, which can often result in a lack of compliance by the patient with the use of injections because of the associated inconvenience and pain.
In recent years research has been undertaken to develop alternate delivery systems for the effective delivery of protein-based drugs. One such promising mode of delivery is pulmonary delivery using an aerosol formulation of the protein-based drug. An advantage of pulmonary delivery of drugs to patients is that this mode is rapid because access to the circulation system is via the lungs, which have a large surface area.
Furthermore, administration of drugs through the lungs can bypass the “first pass effect” or “first pass metabolism” commonly associated with drugs absorbed through the gastrointestinal tract (GIT). This “first pass metabolism” refers to metabolism of drugs that occurs between the GIT and the liver before they are available to the systemic circulation system, whereas absorption via the lung allows drugs to directly enter the systemic circulation system without undergoing “first pass metabolism”.
Administration of the protein to the lungs is more likely to be accepted by patients and is therefore an attractive alternative to injections, as long as the protein can be formed as fine particles, without significant loss of biological activity. Usual criteria for the use of aerosol delivery for the administration of therapeutic drugs to the lungs are that the drug is in particulate form. To function effectively, the biological activity of the protein must be maintained. However, this can be somewhat difficult to achieve because during synthesis of the protein particles, the biological activity of the protein may be compromised by reducing the particle size of the protein to the low micron range.
A common problem in manufacture of such protein particles is unacceptable variation in particle size. This can be particularly difficult to achieve when the particles need to be in the micro-size range. Furthermore, the process conditions to produce the protein particles within the required size specifications can also be difficult to achieve. Moreover, protein-based drugs are even more challenging to produce because proteins tend to be somewhat fragile molecules and their biological activity needs to be maintained.
Known methods involve spray-drying a solution containing the protein. Spray-drying results in evaporation and hence removal of the solvent due to the high temperatures used. As the solvent evaporates, the concentration of the protein increases beyond the level of saturation. Therefore, the protein precipitates out from the solution to form particles. A problem with this process is that the drying step often results in the formation of particles with relatively large particle size ranges. Hence the particle sizes are not uniform. As mentioned above, the non-uniform particle size compromises the effectiveness of the particles for use in aerosol formulations. Furthermore, the precipitated particles tend to have a non-porous structure which means that they have a higher density as compared to particles with a porous structure, which can again have an adverse impact on suitability of these particles being used in aerosol formulations. Although it is possible to form particles with porous structures, highly specialized and complicated systems as well as excipients are needed. Moreover, spray drying can lead to protein degradation due to physical shear forces experienced by the protein solution as it passes through the nozzles and/or exposure to the high temperatures at which the spray dryer is operated at. In order to retain the biological activity of the protein particles, stabilizing agents are needed. However, these stabilizing agents and the above-mentioned excipients may not be suitable for pulmonary delivery and extra toxicity studies may be needed to determine their suitability and safety.
One known method to manufacture insulin micro-particles involves the atomisation of a solution containing a matrix-forming polymer and insulin, and then directing the resulting droplets into a liquefied gas, typically liquid nitrogen. The droplets freeze on contact with the liquefied gas and may then be dried using a freeze-drying step to remove residual moisture. The resulting micro-sized protein particles comprise the insulin dispersed within the polymer matrix. However a problem with this method is that the biological activity of the particles may be compromised during the freeze drying step. Furthermore, because the formed micro-particles are formed by precipitation during the atomization step, it may be difficult to form particles having a substantially uniform particle size. Moreover, excipients are typically added during this process to enhance the stability of the protein during the freezing step and during storage. A problem with adding excipients is that they may be unsuitable for inhalation delivery. Another problem associated with the above process is that it is not easy for scale-up.
There is a need to provide a process of making micro-sized protein particles that overcomes, or at least ameliorates, one or more of the disadvantages described above. There is also a need to provide micro-sized protein particles that are suitable for use in an inhalation device for pulmonary delivery to a patient.